1. Field of the Invention
This invention relates to a medicinal aerosol formulation, and more particularly, to a medicinal aerosol formulation comprising a protective colloid stabilizer.
2. Description of the Related Art
Delivery of drugs to the lung by way of inhalation is an important means of treating a variety of conditions, including such common local conditions as cystic fibrosis, pneumonia, bronchial asthma and chronic obstructive pulmonary disease and some systemic conditions including pain management, immune deficiency, hormonal therapy, erythropoiesis, diabetes, etc. Steroids, (xcex22 agonists, anti-cholinergic agents, proteins and polypeptides are among the drugs that are administered to the lung for such purposes. Such drugs are commonly administered to the lung in the form of an aerosol of particles of respirable size (less than about 10 xcexcm in diameter). In order to assure proper particle size in the aerosol, particles can be prepared in respirable size and then incorporated into a colloidal dispersion containing either a propellant, as a pressurized metered dose inhaler (MDI), or air such as is the case with a dry powder inhaler (DPI). Alternatively, formulations can be prepared in solution or emulsion form in order to avoid the concern for proper particle size in the formulation. Solution formulations must nevertheless be dispensed in a manner that produces particles or droplets of respirable size.
For MDI preparations, once prepared, the aerosol formulation is filled into an aerosol canister equipped with a metered dose valve. In the hands of the patient the formulation is dispensed via an actuator adapted to direct the dose from the valve to the patient.
It is important that an aerosol formulation be stable such that the delivered dose discharged from the metered dose valve is reproducible. Rapid creaming, settling, or flocculation after agitation are common sources of dose irreproducibility in suspension formulations. This is especially true where a binary aerosol formulation containing only medicament and propellant, e.g. 1,1,1,2-tetrafluoroethane, is employed or where such formulation contains small amounts of surfactant as well. Sticking of the valve also can cause dose irreproducibility. In order to overcome these problems, MDI aerosol formulations often contain surfactants, which serve as suspending aids to stabilize the suspension for a time sufficient to allow for reproducible dosing. Certain surfactants also function as lubricants to lubricate the valve to assure smooth actuation. Myriad materials are known and disclosed for use as dispersing aids in aerosol formulations. Suitability of materials, however, is dependent on the particular drug and the propellant or class of propellant used in the formulation.
It is sometimes difficult to dissolve sufficient quantities of conventional surfactants in hydrofluorocarbon (HFC) propellants such as HFC-134a and HFC-227. Cosolvents, such as ethanol, have been used to overcome this problem, as described in U.S. Pat. No. 5,225,183. An alternative approach that avoids cosolvents involves materials that are soluble or homogeneously dispersible in hydrofluorocarbon propellants and are said to be effective surfactants or dispersing aids in an aerosol formulation. Among such materials are certain fluorinated surfactants and certain polyethyoxysurfactants.
Medicaments which are relatively small molecules are much more predictable in terms of their aerosol formulation characteristics than macromolecules. The macromolecules, such as peptides or proteins, which range in molecular size from about 1K Dalton to about 150 K Daltons in molecular size are very unpredictable and present unique problems in forming aerosol formulations thereof which are stable and provide reproducible dosage.
Most peptide and protein drugs, such as hormones, e.g. insulin, amylin, etc., enzymes, antinfectives, are quite variable in their amino acid composition and three-dimensional structure. Consequently their surface activity is highly variable, and importantly, no model is yet available that explains differences in protein surface activity based on their most basic and structural properties, such as molecular weight, adsorptivity, solubility, partition coefficient and isoelectric pH. Hemoglobin, for example, has far higher affinity for solid surfaces than does albumin, yet the molecular weights of these two proteins are very similar. Fundamentally, the diversity in surface activity of peptides and proteins originates in the linear sequence of amino acids that uniquely characterizes each type of protein. The amino acid side chains often vary dramatically in that some carry no charge at any pH, yet exhibit considerable polar character (serene, threonine). Other amino acids are ionizable and vary from fairly acidic (aspartic and glutamic acid are fully negatively charged at the physiological pH of 7.4) to basic functionalities, such as the imidazole group in histidine (which carries a partial positive charge at pH 7.4), and the still more basic amino groups in lysine and arginine that carry full positive charges at pH 7.4. Another group of amino acids, somewhat hydrocarbon-like in character, appear to demonstrate generally a much lower solubility profile in water (tryptophan, phenylalanine, isoluecine, etc.) than many of the other amino acids found in biological systems. It is noteworthy that the hydrophobicity of these water-hating amino acids varies greatly with their specific structure in the protein. For example, the single methyl group side chain in alanine contributes only 0.5 kcal/mole to the free energy of transfer from water to an organic phase, whereas the double-ringed indole group in tryptophan contributes 3.4 kcal. The variety of amino acid side chains, together with the many different types of chemical interactions that result in solution and at surfaces, should be expected to have a considerable impact on aerosol formulation stability as well as transport of these peptide and protein biotherapeutic agents across biologic membranes.
The diverse character of the amino acid side chains, together with the complexity of various combinations of amino acids present in each particular protein, means that physicochemical properties of the proteins, their intermolecular as well as intramolecular Fax reactivity, and also their ability to interact with surfaces should be highly variable. Due to their large size, and correspondingly due to the large numbers of charged amino acid side chains, proteins have many charges distributed over their exterior surface. This could lead to very large variances in aerosol formulation stability and lung uptake of these compounds. Peptide and protein drugs also generally have multiple ionization sites and therefore they often demonstrate pH-dependent solubility profiles. Importantly, the hydrophilic nature of these compounds provides excellent conditions for high aqueous solubility. Consequently, most peptide and protein drugs present extremely low lipid solubility characteristics, the latter possibly being one reason why dispersions of these drugs in hydrofluorocarbon propellants would be physically and chemically stable across a wide range of storage conditions. An aerosol medicament formulation comprising peptide and protein drugs in carrier or formulation media within which they are virtually insoluble is needed to reduce hydrolytic and chemical deactivation usually typical of aqueous solutions.
The combination of a large surface area, thin absorptive carrier, and extensive vasculature constitutes a favorable absorptive environment for proteins and peptides when delivered by the pulmonary route. Studies show that intratracheal (i.t.) administration of peptides is rapid and quantifiable; however the resultant distribution is often localized in central airways. Administration by aerosol, for example, depending on particle size distribution, may be used to give more uniform distribution with greater alveolar penetration. Drug absorption from the airways is dependent upon the site of deposition, the method of drug delivery, the type of solute presentation and composition of the formulation. Therefore, formulation and device characteristics will have a dramatic impact upon the rate and extent of peptide absorption from the lung. Studies show that absorption rates following aerosol delivery of small molecular weight compounds can be roughly twice that of i.t. delivery. What is desired is to present peptides and proteins as hydrophobic dispersions via a multi dose inhalation device (xe2x80x9cpMDIxe2x80x9d) in order to have greater penetration of the drug particles to the peripheral lung where absorption should be significantly greater than it is for centrally deposited drug as is the case with aqueous instillations.
The realty that insulin can be absorbed from the lung into the bloodstream has been demonstrated by a number of scientists. A 1990 review article [Lung, supplement pp. 677-684] demonstrated from multiple studies that aerosolized insulin delivered into the lung yielded a half-life of 15-25 minutes but results were quite variable. Comprehensive studies also have demonstrated that aerosolized insulin given peripherally into the lung of rabbits produced bioavailability of over 50.7 percent in contrast to 5.6 percent bioavailability seen for liquid insulin dripped into the central airways. These studies therefore support the contention that aerosolized insulin must be delivered peripherally into the lung for maximum efficiency and that inadvertent central disposition of inhaled aerosolized insulin will produce an effect ten times lower than that desired. Such variations in dosing of ten-fold are clearly unacceptable if aerosolized insulin should become an effective means of treating diabetes. Thus, there is need for effective, high precision aerosol devices to achieve the tolerances required for aerosolizing insulin to human subjects. This concept for using aerosolized insulin in diabetes management would also apply to amylin and glucagon, partner hormones to insulin in the regulation of plasma glucose concentrations, which until now, must be administered by subcutaneous injection (s.c.).
Dry powder presentations of peptide and protein drugs possess unique opportunities in formulations, which do not occur in liquid presentations such as pMDIs and nebulized solutions. Dry powder aerosols of peptide and protein drugs, because of improved solid state stability, are attractive from the formulation standpoint since many of the undesirable solution and liquid state interactive effects are circumvented. In this regard, reference is made to Rubsamen et al., U.S. Pat. No. 5,672,581 and Patton et al. in U.S. Pat. No. 5,775,320.
Both the Rubsamen and Patton approaches are therapeutically feasible although their complexity and presumed inherent costs limit their applicability to the management of a chronic disease like diabetes mellitus. Thus, it is a problem to use an expensive, complicated device such as the portable, electronically based portable nebulizer to routinely deliver hypoglycemics to patients that need them. It is further a problem to use large, bulky, difficult to clean a dry powder aerosol device like the Patton device to deliver the hypoglycemics to the body via lung. Thus, the primary objective in formulating a peptide or protein drug as a dry powder inhalation aerosol (DPI) is to enable the drug, and in some cases, added excipients, to form an aerocolloid which is chemically and physical stable and can remain in suspension until the drug particle reaches the alveolar or other absorption sites. Once at the absorption site, the drug particles should be efficiently trapped at the deposition site, dissolve rapidly in the epithelial lining fluids, and be absorbed quickly across the biomembrane thereby limiting possible deactivation by metabolizing enzymes in the airways.
Spray drying is a process used to prepare medicament particles for drug formulations. Spray drying constitutes a single step process which transforms a solution or suspension into fine powder. Generally, spray drying produces spherical particles, which are often hollow thus resulting in a powder with low bulk density compared to the initial material. Powder characteristics of spray dried materials (i.e., particle size distribution, bulk density, porosity, moisture content, dispersibility, etc.) are generally good in many regards, but particles manufactured by this process demonstrate poor flow characteristics. Furthermore, a requirement for heat during particle formation by this process makes spray drying less desirable for heat sensitive compounds such as peptide and protein drugs. Thus, it is a problem that most dry powder aerosols demonstrate adhesion and poor flowability through device hardware to the extent that accuracy of dose delivery becomes a problem to the patient.
Another problem associated with peptide and protein formulations as dry powder aerosols is that of packaging the material as agglomerates in a device such that during aerolization, the agglomerates are broken up, and the individual particles released prior to entry into the airways. Preparation of robust agglomerates of micron or sub-micron sized particles is a reasonably straightforward task which can be achieved by conventional granulation, with or without polymeric binders. However, the requirement that upon entering the airways, the agglomerates should break up into primary particles, probably rules out a simple, conventional approach to granulation since the interparticle forces could be too large to allow easy, efficient and prompt deagglomeration. The total adhesive force between two unlike particles or total cohesive force between two like particles can be considered as being constituted from a sum of one or more attractive forces. Many of these forces are known to be responsible for formation of adhesive units between dry powder and excipient particles in formulations. Therefore the aim of any manipulation of inter-particle forces will be to produce agglomerates of between say, 50 and 200 xcexcm diameter, which are robust enough to withstand flow, storage and packing in the delivery device, but which can be de-agglomerated rapidly and completely by the shear stresses in the inspired air stream. This problem which is quite common in peptide and protein aerosol formulations may be avoided completely in liquid formulations within which the drug is insoluble, is presented as a colloidal dispersion, and is sterically protected against self-association. Hence it is a desire to formulate peptide and protein drugs as loose, flocculated colloids in non-aqueous media, like hydrofluorocarbons, which rapidly and easily break up into discrete particles upon aerolization to the airways. Additionally, it is desired to present peptide and protein drugs in formulation systems within which the drug particles are perpetually in random motion, thus eliminating aggregate formation of the individual drug particles.
Other non-injectable diabetes therapies have been proposed, some demonstrating that a biotherapeutic response could be produced following nasal administration of insulin when formulated with detergents and other membrane penetrants, as indicated in Moses et al., Diabetes, Vol. 32, November 1983, and Salzman et al., New England Journal of Medicine, Vol. 312, No. 17. Significant inter-subject variability and irritation of nasal membranes to varying degrees is observed. Since diabetes is a chronic disease which must be continuously treated by the administration of insulin, and since mucosal irritation tends to increase with repeated exposures to membrane penetration enhancers, efforts at developing a non-invasive nasally administered insulin have not been commercialized. Accordingly, a safe, reproducible, effective, non-invasive delivery means for peptide and protein drugs via lung as pMDIs is desired and needed.
It has surprisingly been found that novel and stable medicinal aerosol formulations of macromolecular medicaments can be obtained without the use of either cosolvents, such as ethanol, or surfactants, such as sorbitan trioleate which are added to a binary aerosol formulation of small molecule medicaments. Stable medicinal aerosol formulations are obtained by the use of a protective colloid stabilizer.